Prostate cancer is one of the most commonly diagnosed cancers in men in the United States and a major cause of cancer morbidity and mortality. Throughout its history, the Johns Hopkins Prostate Cancer SPORE has focused on reducing prostate cancer incidence and mortality by translating new laboratory research discoveries into improvements in prostate cancer screening, detection, diagnosis, prevention, and treatment. This competitive renewal proposal contains six new Translational Research Projects, three Core Resources, two Career Development Projects, and two Developmental Research Projects. Project #1 aims to introduce an entirely new imaging/therapy platform featuring the use of tumor-selective promoter driven transgenes; Project #2 hopes to deliver a therapeutic chimeric RNA, featuring an aptamer mediating selective binding to prostate-specific membrane antigen (PSMA) and an siRNA against the DNA-dependent protein kinase, to selectively augment the radiosensitivity of prostate cancer cells; Project #3 plans to exploit the tendency for prostate cancer immune tolerance to become abrogated for a brief period of time following initiation of androgen deprivation therapy as a window for vaccine immunotherapy; Project #4 proposes to follow-up on a successful synthetic lethal functional genomics screen of new molecular drug targets as partners for nucleoside analog DNA methyltransferase inhibitors to deliver treatment combinations to clinical trials for advanced prostate cancer; Project #5 commandeers the tumor-specific homing properties of bone marrow derived mesenchymal stem cells to create a platform for selective delivery and activation of the protoxin PRX302 near prostate cancer cells; Project #6, a population science study, tests the utility of measured telomere lengths in stromal cells and cancer cells in predicting risk for prostate cancer death. These Projects are supported by an Administrative Core, a Pathology/Biospecimen Core, and a Biostatistics/Bioinformatics Core. Finally, the Career Development and Developmental Research Programs, supplemented by $1,000,000 annually from the Patrick C. Walsh Prostate Cancer Research Fund, comprise pipelines of human capital and innovative ideas, respectively, which will fuel future SPORE advances.